Current treatments used to treat various types of cancer tend to work by poisoning or killing the cancerous cell. Unfortunately, treatments that are toxic to cancer cells typically tend to be toxic to healthy cells as well. Moreover, the heterogenous nature of tumours is one of the primary reasons that effective treatments for cancer remain elusive. Current mainstream therapies such as chemotherapy and radiotherapy tend to be used within a narrow therapeutic window of toxicity. These types of therapies are considered blunt tools that have limited applicability due to the varying types of tumour cells and the limited window in which these treatments can be administered.
Modern anticancer therapies currently being developed attempt to selectively target tumour cells while being less toxic to healthy cells, thereby being more likely to leave healthy cells unaffected.
Oncolytic viral therapy is one approach that aims to exploit cellular differences between tumour cells and normal cells. This therapy uses replication-competent, tumour-selective viral vectors as anti-cancer agents. The oncolytic virus either specifically targets cancer cells for infection, or is more suited for efficient replication in cancer cells versus healthy cells. These replication-competent, oncolytic viruses are either naturally occurring or genetically engineered to be a highly selective and highly potent means of targeting the heterogeneous tumour population. Since the replication selective oncolytic virus does not replicate efficiently in normal cells, toxicity to the patient should be low, particularly in comparison to traditional therapies such as radiation or chemotherapy.
Numerous studies have reported oncolytic activity for various virus strains, with the most promising oncolytic viruses being a naturally occurring or genetically modified version of adenovirus, herpes simplex virus 1 (“HSV1”), Reovirus, Vaccinia Virus, Vesicular Stomatitis Virus (“VSV”) or Poliovirus. Modified oncolytic viruses currently under investigation as anticancer agents include HSV, adenovirus, Newcastle disease virus (“NDV”), Reovirus and Vaccinia virus, measles, VSV and poliovirus. Various oncolytic viruses are in Phase I and Phase II clinical trials with some showing sustained efficacy. However, it is unknown which viruses will best fulfill the oncolytic goals of sustained replication, specificity and potent lytic activity. A completely efficient candidate for an oncolytic viral vector would be one that has a short lifecycle, forms mature virions quickly, spreads efficiently from cell to cell and has a large genome ready for insertions. As well, evidence suggests that inhibiting the early innate immune response and slowing the development of Th1 responses are important for the efficacy of oncolytic therapy. It is clear that human viruses are highly immunogenic, as measured by the high level of antibody and T cell responses that are observed in the normal population for many of the viruses being considered for the development of oncolytic viruses.
Clinical work has shown that current oncolytic viruses are indeed safe, but are not potent enough as monotherapies to be completely clinically effective. As insufficient or inefficient infection of tumour cells is usually observed, the current movement is to arm candidate viruses by genetically engineering them to express therapeutic transgene to increase their efficiency. Most of the above-mentioned oncolytic viruses are also being tested in combination with other common oncolytic therapies.
Adenovirus can be easily genetically manipulated and has well-known associated viral protein function. In addition, it is associated with a fairly mild disease. The ONYX-015 human adenovirus (Onyx Pharmaceuticals Inc.) is a one of the most extensively tested oncolytic viruses that has been optimized for clinical use. It is believed to replicate preferentially in p53-negative tumours and shows potential in clinical trials with head and neck cancer patients. However, reports show that ONYX-015 has only produced an objective clinical response in 14% of treated patients (Nemunaitis J, Khuri F, Ganly I, Arseneau J, Posner M, Vokes E, Kuhn J, McCarty T, Landers S, Blackburn A, Romel L, Randlev B, Kaye S, Kirn D. J. Clin. Oncol. 2001 Jan. 15; 19(2):289-98).
WO96/03997 and WO97/26904 describe a mutant oncolytic HSV that inhibits tumour cell growth and is specific to neuronal cells. Further advantages are that the HSV can be genetically modified with ease and drugs exist to shut off any unwanted viral replication. However, the application of such a common human pathogen is limited, as it is likely that the general population has been exposed and acquired an immune response to this virus, which would attenuate the lytic effect of the virus. HSV can also cause serious side effects or a potentially fatal disease.
Reovirus type III is associated with relatively mild diseases and its viral gene function is fairly well understood. Reovirus type III is currently being developed by Oncolytic Biotech as a cancer therapeutic which exhibits enhanced replication properties in cells expressing mutant ras oncogen and preferentially grows in PKR−/− cells (Strong J. E. and P. W. Lee, J. Virology, 1996. 70:612-616). However, Reovirus is difficult to genetically manipulate and its viral replication cannot be easily shut off.
VSV is associated with relatively mild diseases and also has well-known viral gene function. WO99/04026 discloses the use of VSV as a vector in gene therapy for the expression of wide treatment of a variety of disorders. However, VSV suffers from the same problems as the Reovirus in that it is difficult to genetically manipulate and its viral replication cannot be easily shut off.
Vaccina virus and Poliovirus are other candidate oncolytic viruses described in the art but have been associated with a serious or potentially fatal disease.
U.S. Pat. No. 4,806,347 discloses the use of gamma interferon and a fragment of IFNγ against human tumour cells. WO99/18799 discloses a method of treating disease in a mammal in which the diseased cells have defects in an interferon-mediated antiviral response, comprising administering to the mammal a therapeutically effective amount of an interferon-sensitive, replication competent clonal virus. It specifically discloses that VSV particles have toxic activity against tumour cells but that alleviation of cytotoxicity in normal cells by VSV occurs in the presence of interferon. WO99/18799 also discloses that NDV-induced sensitivity was observed with the interferon-treated tumour cells but that adding interferon to normal cells makes these cells resistant to NDV. This method aims to make cells sensitive to interferon by infecting them with interferon sensitive viruses.